CN1647799A - Toad extract liposome preparation for injection and its preparing method - Google Patents
Toad extract liposome preparation for injection and its preparing method Download PDFInfo
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- CN1647799A CN1647799A CNA2004100160647A CN200410016064A CN1647799A CN 1647799 A CN1647799 A CN 1647799A CN A2004100160647 A CNA2004100160647 A CN A2004100160647A CN 200410016064 A CN200410016064 A CN 200410016064A CN 1647799 A CN1647799 A CN 1647799A
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- bufo siccus
- lecithin
- cholesterol
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- 239000000284 extract Substances 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 238000002347 injection Methods 0.000 title claims abstract description 16
- 239000007924 injection Substances 0.000 title claims abstract description 16
- 238000000034 method Methods 0.000 title claims description 5
- 239000002502 liposome Substances 0.000 title abstract description 16
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract description 50
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims abstract description 25
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 25
- 229940067606 lecithin Drugs 0.000 claims abstract description 25
- 235000010445 lecithin Nutrition 0.000 claims abstract description 25
- 239000000787 lecithin Substances 0.000 claims abstract description 25
- 241000269417 Bufo Species 0.000 claims description 56
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- 229950006858 bufogenin Drugs 0.000 description 2
- VTTONGPRPXSUTJ-UHFFFAOYSA-N bufotenin Chemical compound C1=C(O)C=C2C(CCN(C)C)=CNC2=C1 VTTONGPRPXSUTJ-UHFFFAOYSA-N 0.000 description 2
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The toad extract liposome preparation for injection includes toad extract in effective amount, lecithin and cholesterol. Experiment shows that the preparation has toxicity obviously lower than available product, high treating effect, targeting treatment effect and homogeneous distribution of product grain size, and may be used in treating several kinds of tumor.
Description
Technical field
The present invention relates to a kind of pharmaceutical preparation that contains Bufo siccus extract, particularly contain the injection medicine preparation of Bufo siccus extract.
Background technology
Bufo siccus is the Amphibia anuran, and kind more than 250 is arranged, and it is very wide to distribute, and wherein a fairly large number of is Bufo siccus and Bufo melanostictus.The extract of its skin, glandular integumentaria and ear rear gland, sweet in the mouth, suffering, warm in nature.Toxin expelling, detumescence, heart tonifying, pain-relieving functions are arranged.Cure mainly malignant boil, diseases such as carbuncle, laryngopharynx swelling and pain.
Bufo siccus extract main component cardiotonic glycoside is the Venenum Bufonis poison, after its hydrolysis kind of bufotalin surplus 10.As: magnificent Toadpoison Medicine, magnificent bufotoxin, cinobufagin, hydroxyl cinobufagin, Toadpoison Medicine.Indole derivatives: bufotenine, the plain methine of toad, 5-hydroxy tryptamine, epinephrine etc.See (modern Chinese medicine pharmacology, Wang Benxiang chief editor, Tianjin science tech publishing house for details.1997, P1411).
Bufo siccus fat extract has certain clinical effectiveness to multiple cancer, especially to Lymphocytic leukemia (Jiang Kaixian chief editor, the clinical and research of Venenum Bufonis, TCM Document, Maritime Press, Beijing, 1994, P58).
The aqueous extract of Bufo siccus is to the neural collagenoma of the people of In vitro culture, hepatocarcinoma, cell such as leukemia and uterus carcinoma has inhibitory action (Zhang Yuyao, Xu Changzhao: the experimentation of the total composition of Venenum Bufonis water solublity, Nanjing Chinese medicine institute journal, 1998,7 (2): 33) (Yang Sujuan, the clinical practice of Bufo siccus and Venenum Bufonis and progress, Chinese medicine magazine, 1992,9 (5): 2).
The injection made from the Bufo siccus extract bufogenin is mainly used in respiratory stimulant at Japanese existing procucts, can increase the rich output of heart, adds high ventilating rate, and the effect of strengthening heart and boosting pressure is arranged.The domestic liquid drugs injection that Bufo siccus severe edema due to hypofunction of the spleen dissolubility extract is arranged, HUACHANSU ZHUSHEYE, Venenum Bufonis Injection, major function is a detoxicating, relieving inflammation, infect as acute, chronic purulent, antitumor, anticancer adjuvant drug has the general body state of improvement, recover cellular immune function, improve effects such as leukocyte level.The main effect of the oil of Bufo siccus, water extract is a heart tonifying, but also is main toxic action part.Because of its valid density is lower, limited its use.
Summary of the invention
The technical issues that need to address of the present invention are to disclose a kind of injection Bufo siccus extract Liposomal formulation and preparation method thereof, have circumscribed defective to overcome the use that prior art exists.
Technical conceive of the present invention is such:
Liposome can wrap up fat-soluble and two types of medicines of water solublity, and it is the direction-sense pharmaceutical carrier with multiple function.Liposome itself is little to human toxicity, and liposome do not have immunosuppressive action to human body, makes medicine have the targeting feature of directional profile in vivo.Medicine is encapsulated in liposome, can reduce drug toxicity.Because medicine is mainly absorbed by the phagocyte of reticuloendothelial system by after liposomal encapsulated, in the more rich organs of reticuloendothelial cell such as liver, spleen and bone marrow, concentrate, and the cumulant specific ionization medicine of medicine in heart and kidney is much lower.Therefore, as with those to heart, the virose medicine of kidney, especially to the virose antitumor drug of normal cell, be encapsulated as the toxicity that liposome can obviously reduce medicine.
For this reason, the inventor is through a large amount of tests, developmental research a kind of be the injection Bufo siccus extract Liposomal formulation of carrier with the liposome, to satisfy the needs of medical field.
Injection Bufo siccus extract Liposomal formulation of the present invention comprises Bufo siccus extract and the lecithin and the cholesterol for the treatment of effective dose, and wherein: the consumption between lecithin and the cholesterol is: 3～20 parts in lecithin, 0～10 part in cholesterol, weight portion;
Preferred ingredients and parts by weight comprise:
1 part in cholesterol
3～20 parts in lecithin
0.1～10 part of Bufo siccus extract
The effect of cholesterol is that the film-strength of liposome is increased, and to increase the stability of liposome, the effect of lecithin provides bilayer, contains medicine, and both are as the carrier of Liposomal formulation;
Said Bufo siccus extract comprises the Bufo siccus liposoluble extract or/and water solubility extract.
The liposoluble extract of being addressed refers to the effective ingredient that adopts water-insoluble organic solvent to extract from Bufo siccus, extracting method is existing play-by-play in numerous documents, and the present invention repeats no more.
The water solubility extract of being addressed is solvent with water, the effective ingredient that extracts from Bufo siccus is mainly indoles alkaloid and derivant thereof, existing detailed introduction in aforesaid document, extracting method is existing play-by-play in numerous documents, and the present invention repeats no more.Also can adopt the commercially available prod.
Toadpoison Medicine＜bfifalin is called for short BF), be one of the anti-midship tumor of liposoluble extract effect main component of Bufo siccus, can delay the life cycle of the growth rate and the prolong rats of rat implantation tumour.Toadpoison Medicine can optionally induce sick cell differentiation of human leukemia and accent to die, and cell in vitro is cultivated proof, and Toadpoison Medicine is 10
-7～10
-5Inducing leukemia natural death of cerebral cells during M is 10
-9～10
-8Inducing leukemia cell differentiation then during M, and can recover the sensitivity of anti-clinically retinoic acid leukaemia to retinoic acid.Share with other antineoplastic agent, can improve the sensitivity of tumor cell antitumor drug.Although the above-mentioned mechanism of action of Toadpoison Medicine is still not fully aware of, may can to change the activity of mitogen-activated protein kinase in the cell (MAPK) relevant with Toadpoison Medicine, and then influence the expression of some oncogene.
Toadpoison Medicine is a hydrophobic drug, mouse peritoneal injection LD
50Be 2.2mg/kg, at present as yet not separately as medicinal application.
Said indoles alkaloid and derivant thereof are 30～63% (Sha Jingzhu to the suppression ratio of zoografting tumor, Mao Hongkui, HUACHANSU ZHUSHEYE, the pharmacy circular, 1987,22 (7): 438), be used for digestive system carcinomas such as hepatocarcinoma clinically, curative effect (Xuan Dianfa, Zhou Min preferably arranged, cinobufacin treatment primary hepatocarcinoma 69 routine short term effect preliminary observations, the combined therapy of Chinese and Western medicine, 1985,5 (2): 126), discovery cinobufacins such as Zhang Zhen is own have direct lethal effect to three kinds of digestive tract tumor, and effect and cisplatin are suitable.Site of action is at intracellular DNA, (Zhang Zhen oneself etc., cinobufacin is to three kinds of digestive tract tumor's cell killing Mechanism Study, Pharmacology and Clinics of Chinese Materia Medica, 1995,15 (5): experimentation.
According to the present invention, when being active component, being preferably in and adding 10～30 parts in dextran or mannitol in the above-mentioned composition again with the Bufo siccus water solubility extract, with support, form good preparation as dried frozen aquatic products.
The preparation method of above-mentioned injection Bufo siccus extract Liposomal formulation comprises the steps: when being active component with the Bufo siccus liposoluble extract
Get lecithin, cholesterol and Bufo siccus liposoluble extract such as Toadpoison Medicine are dissolved in organic solvent, and organic solvent is removed in decompression under 10～50 ℃ temperature again, adding water for injection handled in ultrasonic water bath 5～60 minutes, the high pressure homogenize is filtered, and adopts conventional method lyophilization to get final product.
The organic solvent of being addressed comprises chloroform or ethanol, preferred chloroform.
The preparation method of above-mentioned injection Bufo siccus extract Liposomal formulation comprises the steps: when being active component with the Bufo siccus water solubility extract
Lecithin, cholesterol with dissolve with ethanol after, dropwise splash into logical N
2The aqueous solution that is dissolved with Bufo siccus fat aqueous extract and dextran or mannitol that stirs rapidly, adopt conventional method lyophilization to get final product then.
When being active component as the while with Bufo siccus liposoluble extract and Bufo siccus water solubility extract, the preparation method of stating injection Bufo siccus extract Liposomal formulation comprises the steps:
(1) with cholesterol, lecithin and Bufo siccus liposoluble extract are dissolved in organic solvent such as the chloroform, heat in 10～50 ℃ of water-baths, remove chloroform and get the pastille immobilized artificial membrane;
(2) with lecithin, cholesterol with dissolve with ethanol after, dropwise splash into logical N
2The aqueous solution that is dissolved with Bufo siccus fat aqueous extract and dextran or mannitol that stirs rapidly;
(3) product with step (1) and step (2) adds in the entry, stirs down logical N
2Make dissolving, the high pressure homogenize is crossed 0.45u, behind the filter membrane of 0.2u, adopts conventional method lyophilizing to get final product.
Preparation of the present invention can be used for treating diseases such as hepatocarcinoma, pulmonary carcinoma, digestive tract tumor or leukemia, and general dosage＞3 μ g/kg body weight can be according to the state of an illness and patient decision, by intravenous injection.
Test data proves that preparation toxicity of the present invention is starkly lower than existing product, and therapeutic effect is good, and has the targeted therapy effect, and product cut size is evenly distributed.
Description of drawings
Fig. 1 is for being the liposome particle size distribution of active component with the Toadpoison Medicine.
The specific embodiment
Embodiment 1
Prescription:
Lecithin 5 grams, cholesterol 1 gram; Toadpoison Medicine 1 gram.
Preparation technology:
Get lecithin, cholesterol and Bufo siccus liposoluble extract such as Toadpoison Medicine are dissolved in the 18ml chloroform, and chloroform is removed in decompression under 40 ℃ temperature again, add water for injection 100ml, in ultrasonic water bath, handled 15 minutes the high pressure homogenize, filter, adopt conventional method lyophilization.
Its particle size distribution such as Fig. 1, the particle size distribution figure of Fig. 1 for recording with laser diffractometry, from scheming as seen, mean diameter is 80nm, does not see the particle greater than 200nm.
Embodiment 2
Prescription:
Lecithin 8 grams, cholesterol 1 gram, Bufo siccus water solubility extract 0.5 gram, Dextran 10 gram.
Preparation technology:
After lecithin, cholesterol are used the 15ml dissolve with ethanol, dropwise splash into logical N
2Stir rapidly be dissolved with Bufo siccus fat aqueous extract and dextran aqueous solution 200ml, use 5u, 0.45u, the membrane filtration of 0.2u adopts the method lyophilization of routine to get final product then.The particle size distribution that records with laser diffractometry is: mean diameter is 80nm, does not see the particle greater than 500nm.
Embodiment 3
Prescription:
(A) part: lecithin 9 grams, cholesterol 2 grams, Toadpoison Medicine 1 gram, bufogenin 0.5 gram, cinobufacin 0.14 gram.
(B) part: lecithin 5 grams, cholesterol 1 gram, Bufo siccus water solubility extract 0.5 gram, Dextran 10 gram or mannitol 20 grams.
Preparation technology:
(1) all material with (A) part is dissolved in the chloroform, reduces pressure in 40 ℃ of water-baths, removes chloroform and gets the pastille immobilized artificial membrane;
(2) with lecithin, cholesterol with dissolve with ethanol after, dropwise splash into logical N
2Stir rapidly be dissolved with Bufo siccus fat aqueous extract and dextran aqueous solution or Osmitrol;
(3) product with step (1) and step (2) adds in the entry, stirs down logical N
2Make dissolving, the high pressure homogenize is crossed 0.45u, behind the filter membrane of 0.2u, adopts conventional method lyophilizing to get final product.
The mean diameter that records with laser diffractometry is 70～80nm, and 99.5% particle is less than 200nm.
Embodiment 4
The acute toxicity of the bufalin liposome of embodiment 1:
The LD of free Toadpoison Medicine
50: 1.64 (1.5～1.8); The LD of embodiment 1
50: 3.68 (3.4～3.9)
The toxicity of bufalin liposome obviously descends, may be because they be many in the distribution of network structure endothelial system, and the heart place is few, and lymphsystem concentration height, main concentration reduces relevant.Therefore prompting may reduce its cardiac toxicity, and improves antitumor action.
Embodiment 5
Effect to anti-Mice Bearing Lewis Lung Cancer in the body of the bufalin liposome of embodiment 1 is tested, and the results are shown in following table:
| The administration group | Dosage mg/kg) | Mus number before and after the treatment is front/rear | The weight front/rear (g) of Mus before and after the treatment | Heavy X ± the SD (g) of tumor | Suppression ratio % |
| Normal saline | 0 | 10/10 | 19.2?/?22.7 | 2.76±0.35 | 0 |
| Bufalin liposome | 0.33 | 10/10 | 19.3/21.2 | 1.47±0.35 | 56.74 |
| 5-fluorouracil | 25 | 10/10 | 19.5/20.5 | 1.26±0.25 | 54.38 |
Embodiment 6
The acute toxicity of the preparation of embodiment 2:
The LD of Bufo siccus water extract
50: 1.3mg/kg; The LD of embodiment 2
50: 4.6mg/kg.
This shows that the liposome toxicity of embodiment 2 obviously descends, and helps antineoplaston.
Embodiment 7
The stability of formulation test of embodiment 3.
The compound formulation of embodiment 3 is placed 40 ℃, under the condition of 75%RH, situation of change behind the different time such as following table.
| Standing time | Particle size distribution | Toadpoison Medicine content (%) | Total indole alkali content (%) | |
| Mean diameter (nm) | Maximum particle diameter (nm) | |||
| ????0 | ????70 | Do not see greater than 500 | ????100.0 | ????100.0 |
| ????1 | ????80 | Do not see greater than 500 | ????98.8 | ????98.9 |
| ????2 | ????75 | Do not see greater than 500 | ????99.0 | ????97.9 |
| ????3 | ????75 | Do not see greater than 500 | ????99.4 | ????99.0 |
Stability test shows that the preparation of embodiment 3 is stable in 3 each months.
Claims (8)
1. injection Bufo siccus extract Liposomal formulation is characterized in that comprising Bufo siccus extract and the lecithin and the cholesterol for the treatment of effective dose, and wherein: the consumption between lecithin and the cholesterol is: 3～20 parts in lecithin, 0～10 part in cholesterol, weight portion.
2. preparation according to claim 1 is characterized in that component and parts by weight comprise:
1 part in cholesterol
3～20 parts in lecithin
0.1～10 part of Bufo siccus extract.
3. preparation according to claim 1 and 2 is characterized in that, said Bufo siccus extract comprises the Bufo siccus liposoluble extract or/and water solubility extract.
4. preparation according to claim 1 and 2 is characterized in that, also comprises 10～30 parts in dextran or mannitol, and said Bufo siccus extract is the Bufo siccus water solubility extract.
5. preparation according to claim 3 is characterized in that, also comprises 10～30 parts in dextran or mannitol, weight portion.
6. the preparation method of preparation according to claim 1 and 2 is characterized in that, comprises the steps:
Get lecithin, cholesterol and Bufo siccus extract are dissolved in organic solvent, and organic solvent is removed in decompression, add water for injection and handle in ultrasonic water bath minute, and the high pressure homogenize is filtered, and adopts the method lyophilization of routine to get final product;
The organic solvent of being addressed comprises a kind of in chloroform or the ethanol, and described Bufo siccus extract is a liposoluble extract.
7. the preparation method of preparation according to claim 1 and 2 is characterized in that, the preparation method of above-mentioned injection Bufo siccus extract Liposomal formulation comprises the steps: when comprising the steps: to be active component with Bufo siccus fat aqueous extract
Lecithin, cholesterol with dissolve with ethanol after, splash into logical N
2The aqueous solution that is dissolved with Bufo siccus extract and dextran or mannitol of stirring, adopt conventional method lyophilization to get final product then;
Said Bufo siccus extract is the water solublity Bufo siccus extract.
8. the preparation method of preparation according to claim 3 is characterized in that, comprises the steps:
(1) with cholesterol, lecithin and Bufo siccus liposoluble extract are dissolved in organic solvent, and organic solvent is removed in 10～50 ℃ of heating, get the pastille immobilized artificial membrane;
(2) with lecithin, cholesterol with dissolve with ethanol after, splash into logical N
2The aqueous solution that is dissolved with Bufo siccus fat aqueous extract and dextran or mannitol of stirring;
(3) product with step (1) and step (2) adds in the entry, stirs down logical N
2Make dissolving, the high pressure homogenize behind the filter membrane, adopts conventional method lyophilizing to get final product.
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| CNB2004100160647A CN1290489C (en) | 2004-01-29 | 2004-01-29 | Toad extract liposome preparation for injection and its preparing method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1846712B (en) * | 2006-01-16 | 2012-01-11 | 西安安健药业有限公司 | Cinobufagin emulsion for injection and its preparation process |
| CN1985851B (en) * | 2006-08-07 | 2012-01-25 | 沈阳药大医药发展有限公司 | Lipoid microsphere injection containing toad cake extract and its preparing method |
| CN114432247A (en) * | 2022-01-18 | 2022-05-06 | 南京中医药大学 | A kind of bufatryptamine liposome and its preparation method and application |
-
2004
- 2004-01-29 CN CNB2004100160647A patent/CN1290489C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1846712B (en) * | 2006-01-16 | 2012-01-11 | 西安安健药业有限公司 | Cinobufagin emulsion for injection and its preparation process |
| CN1985851B (en) * | 2006-08-07 | 2012-01-25 | 沈阳药大医药发展有限公司 | Lipoid microsphere injection containing toad cake extract and its preparing method |
| CN114432247A (en) * | 2022-01-18 | 2022-05-06 | 南京中医药大学 | A kind of bufatryptamine liposome and its preparation method and application |
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| Publication number | Publication date |
|---|---|
| CN1290489C (en) | 2006-12-20 |
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